Project Summary/Abstract: The overall goal of this proposal is to evaluate the novel concept whether using lentiviral-engineered T cells that express high affinity T cell receptor (TCR) capable of recognizing the tyrosinase:368-376 epitope, a melanoma/melanocytes differentiation tumor associated antigen have improved efficacy for melanoma immunotherapy. According to the American Cancer Society melanoma is currently the 6th most common cancer in American men and the 7th most common in American women. In this proposal, we will test the fundamental hypothesis that human T cells with redirected specificity for melanoma can be created by using lentiviral vector technology and can offer a clinically relevant and successful therapeutic approach. The ultimate goal is the development of a novel and improved therapy for melanoma, a type of tumor for which the current therapies do not offer satisfactory results. Lentiviral vectors (LVs) have been successfully evaluated in Phase l clinical trials in patients with HIV/AIDS, offering the possibility to more broadly apply this technology for the treatment of other diseases, particularly cancer. Lentigen's collaborator Dr. Michael Nishimura has helped pioneer adoptive immunotherapy as a potential therapeutic approach for melanoma. Therefore, in Aim 1 of this proposal, we will develop self inactivating (SIN) LVs expressing a and B chains of the TCR capable of recognizing the tyrosinase: 368-376 epitope. In Aim 2, together with Dr. Nishimura's team, we will test safety and efficacy of LV-TCR transduced T cells in preventing melanoma tumor growth and treating established tumors in vivo. We will carry out 2 general types of experiments in order to test the in vivo efficacy and engraftment potential of our lentiviral vectors expressed in engineered human T cells. In summary, Lentigen Corp. and Dr. Nishimura's laboratory are uniquely positioned to provide the first comprehensive evaluation of the redirected T cell approach to generate anti-tumor effects in melanoma patients and to apply this in a future clinical trial for patients with this life threatening malignancy. Project Narrative: The ultimate goal of this proposal is the development of a novel and improved immunotherapy therapy for melanoma, a tumor for which the current therapies do not offer satisfactory results. This therapy is based on activation of immune cells that will be manipulated in the laboratory and put back to patient to fight melanoma tumor cells. Because of its great potential to offer a solution for those patients failing other therapies, this therapy will have significant relevance for cancer patients with melanoma and health care providers in the United States and worldwide. [unreadable] [unreadable] [unreadable]